L1CAM-dependent NFκB activation upregulates fascin expression and augments tumor cell invasion and motility

Abstract

Cell migration and invasion are fundamental components of tumor cell metastasis, which contributed to the poor prognosis of hepatocellular carcinoma (HCC). Establishment of a pair of metastatic HCC cell lines (MHCC97L and MHCC97H) provide an indispensable tool to study the molecular mechanism of HCC metastasis. By comparing the genetic alterations between these two cell lines by cDNA microarray analysis, we identified the neuronalcell adhesion molecule L1- mediated signalling as a key event HCC metastasis. L1CAM was significantly associated with HCC metastasis in HCC tissue microarray (p<0.001). Ectopic L1CAM increased HCC cell motility and invasion by modulation of F-actin structure, and induced HCC metastasis in a metastatic HCC nude mice model. Fascin, a key actin binding protein, was first identified as a downstream target of L1CAM mediated HCC cell motility and invasiveness.L1CAM over-expression was significantly correlated with fascin expression in tissue microarray (p=0.007). L1CAM was found to activate fascin promoter through NFκB activation. The RGD sites in the Ig domain 6 of L1CAM was responsible for NFκB dependent fascin over-expression by interaction with αvβ5, augmenting HCC cell invasion and motility. In conclusion, our results demonstrated the significance of L1CAM in HCC. Fascin is an important for L1CAM mediated downstream effects, augmenting cell motility and invasiveness.